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Cerebrospinal fluid sodium rhythms

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Cerebrospinal fluid (CSF) sodium levels have been reported to rise during episodic migraine. Since migraine frequently starts in early morning or late afternoon, we hypothesized that natural sodium chronobiology may predispose susceptible persons when extracellular CSF sodium increases. Since no mammalian brain sodium rhythms are known, we designed a study of healthy humans to test if cation rhythms exist in CSF. Methods Lumbar CSF was collected every ten minutes at 0.1 mL/min for 24 h from six healthy participants. CSF sodium and potassium concentrations were measured by ion chromatography, total protein by fluorescent spectrometry, and osmolarity by freezing point depression. We analyzed cation and protein distributions over the 24 h period and spectral and permutation tests to identify significant rhythms. We applied the False Discovery Rate method to adjust significance levels for multiple tests and Spearman correlations to compare sodium fluctuations with potassium, protein, and osmolarity. Results The distribution of sodium varied much more than potassium, and there were statistically significant rhythms at 12 and 1.65 h periods. Curve fitting to the average time course of the mean sodium of all six subjects revealed the lowest sodium levels at 03.20 h and highest at 08.00 h, a second nadir at 09.50 h and a second peak at 18.10 h. Sodium levels were not correlated with potassium or protein concentration, or with osmolarity. Conclusion These CSF rhythms are the first reports of sodium chronobiology in the human nervous system. The results are consistent with our hypothesis that rising levels of extracellular sodium may contribute to the timing of migraine onset. The physiological importance of sodium in the nervous system suggests that these rhythms may have additional repercussions on ultradian functions.
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Harringtonet al.Cerebrospinal Fluid Research2010,7:3 http://www.cerebrospinalfluidresearch.com/content/7/1/3
CEREBROSPINAL FLUID RESEARCH
R E S E A R C HOpen Access Cerebrospinal fluid sodium rhythms 1* 23 11 2 Michael G Harrington, Ronald M Salomon , Janice M Pogoda , Elena Oborina , Neil Okey , Benjamin Johnson , 2 14 Dennis Schmidt , Alfred N Fonteh , Nathan F Dalleska
Abstract Background:Cerebrospinal fluid (CSF) sodium levels have been reported to rise during episodic migraine. Since migraine frequently starts in early morning or late afternoon, we hypothesized that natural sodium chronobiology may predispose susceptible persons when extracellular CSF sodium increases. Since no mammalian brain sodium rhythms are known, we designed a study of healthy humans to test if cation rhythms exist in CSF. Methods:Lumbar CSF was collected every ten minutes at 0.1 mL/min for 24 h from six healthy participants. CSF sodium and potassium concentrations were measured by ion chromatography, total protein by fluorescent spectrometry, and osmolarity by freezing point depression. We analyzed cation and protein distributions over the 24 h period and spectral and permutation tests to identify significant rhythms. We applied the False Discovery Rate method to adjust significance levels for multiple tests and Spearman correlations to compare sodium fluctuations with potassium, protein, and osmolarity. Results:The distribution of sodium varied much more than potassium, and there were statistically significant rhythms at 12 and 1.65 h periods. Curve fitting to the average time course of the mean sodium of all six subjects revealed the lowest sodium levels at 03.20 h and highest at 08.00 h, a second nadir at 09.50 h and a second peak at 18.10 h. Sodium levels were not correlated with potassium or protein concentration, or with osmolarity. Conclusion:These CSF rhythms are the first reports of sodium chronobiology in the human nervous system. The results are consistent with our hypothesis that rising levels of extracellular sodium may contribute to the timing of migraine onset. The physiological importance of sodium in the nervous system suggests that these rhythms may have additional repercussions on ultradian functions.
Background Many behaviorally related dynamical processes in the nervous system are characterized by episodes of com plex oscillatory states whose periodicity may be expressed over multiple temporal and spatial scales [1]. Mood [2] and manialike behavior [3] have been induced by disruption of the CLOCK gene, and a food entrainable circadian rhythm was found to be regulated by a dorsomedial hypothalamic oscillator [4]. Intrinsic fluctuations within cortical systems account for variabil ity in evoked brain responses [5], yet little is known of the chronobiology of many brain components and it is not known whether pathophysiological symptoms of many diseases are causally linked to circadian rhythms or to other diurnal behaviors [6].
* Correspondence: mghworks@hmri.org 1 Molecular Neurology Program, Huntington Medical Research Institutes, Pasadena, CA, 91101, USA
Migraine commonly has an onset in early morning or late afternoon, suggesting an underlying biochemical rhythm may predispose to this temporal variability [711]. We discovered that CSF sodium concentration + ([Na ]csf) increased during migraine while blood plasma + sodium concentration did not change [12]. [Na ]csfis rapidly equilibrated with extracellular sodium concentra + tion ([Na ]e) [1315] and we recently proposed a + mechanism for the higher [Na]csfin migraine based on increased activity of capillary endothelial cell sodium potassium ATPase (NKAT) [16]. Many other chronobio logical events may be involved in migraine onset, includ ing serotonin that was shown to rise markedly at night in nonhuman primates, and is light regulated [17]. Many lines of evidence have implicated serotonin in migraine and serotonin agonists are in the front line of treatment [18]. Whatever the biochemical mechanism that determines migraine onset, we consider that a
© 2010 Harrington et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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